Good Laboratory Practice Regulations Third Edition Revised and Expanded

Fully updated and revised to include the latest information since publication of the first edition in 1989, the Second Edition of this highly praised reference covers all aspects of the Food and Drug Administration''s (FDA) Good Laboratory Practice (GLP) regulations and techniques for implementation. The book details specific standards and general guidelines for the management of efficient and effective research environment. A guide to the current standards and requirements of good laboratory management, the book examines essential theoretical principles for anticipating new and emerging interpretations of GLP in a variety of laboratory settings.

Marcel Dekker, Inc New York•Basel

Good Laboratory Practice Regulations

Third Edition, Revised and Expanded

edited by Sandy Weinberg

Muhlenberg College Allentown, Pennsylvania, U.S.A.

Copyright © 2003 Marcel Dekker, Inc.

Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress.

ISBN: 0-8247-0891-1

This book is printed on acid-free paper.

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The Good Laboratory Practices (GLPs) are extremely tive guidelines intended to provide management with a toolfor controlling regulated laboratories and to provide regula-tors with a measurement guide for the evaluation of thosecontrolling efforts Over the past decade the GLPs havesurvived the test of field scrutiny and have evolved into ameaningful set of standards for a variety of laboratoriesworldwide

effec-The effects of evolution on regulation are generally tive Vague requirements are clarified with example, disputeresolution, and dissemination of interpretation Differences

posi-of opinion are debated, discussed, and synthesized lines are issued, investigators are trained, and examples areprovided

Guide-Working in conjunction with this delineation of tion are the variances created by changes in practice, technol-ogy, and focus The conjunction of these forces may create itsown conflict, but experience and time have a soothing influ-ence even on disagreement; positions and opinions may be atvariance, but they are at least clear and specific

regula-The GLP regulations have reached this next stage ofevolved understanding The requirements are clear, theguidelines and interpretations are available, and the conflictsare resolved Even the revolutionary influences of computer-ization in the laboratory have been measured and considered,providing the good automated laboratory practices corollaryguidelines The GLPs have come of age, and provide a clearand consistent framework for the assurance of quality andcontrol in the laboratory.

This maturity has led to global GLPs that are, if notidentical, at least compatible In the United States, the samegeneral guidelines apply to laboratories regulated by theFood and Drug Administration (FDA), Environmental Protec-tion Agency (EPA) labs, and general analytical laboratories.Those same standards are consistent with required proce-dures in the European Community (EC); Switzerland, Japan,Israel, Brazil, and Russia The Worldwide concern for qualityand control had evolved the same general principles of opera-tion and organization

This third edition of Good Laboratory Practice tions reflects that evolutionary maturity of requirements.

Regula-With a relative uniformity of interpretation more specificand applied information can be provided, furnishing thereader with both the theoretical overview necessary to an-ticipate new and emerging interpretations and the detail ofpractical information that can serve as a guide to the cur-rent standards and requirements of good laboratory manage-ment

Chapter 1 provides a historical review of the ary process, tracing the problems and concerns of regulatorsand the response of laboratory managers to those issues Theultimate result, is the series of guidelines published as theGLPs, provided with a context and rationale

evolution-Chapter 2 provides a definitive review of the current sion of FDA GLPs, including an analysis and interpretation

ver-of the enforcement ver-of the GLPs This summary is an excellent

overview for readers not previously familiar with the ments.

require-Chapter 3 examines the new FDA regulation, Part 11,and its impact on a GLP laboratory setting This chapter ar-gues that Part 11 is a de facto extension of the GLPs andrepresents a historical update of the GLP regulation

Chapters 4 and 5 focus on two important applications ofthe GLPs In Chapter 4 the GLPs are applied to an auto-mated laboratory as the (EPA) good automated laboratorypractices Chapter 5 examines the impact and interpretation

of the GLPs in a non-GLP analytical laboratory StephanieOlexa makes an impressive case that the GLPs are relevantguidelines even where they are not regulatory requirements.Chapter 6 provides specific standards and general guide-lines for the validation of Laboratory Information Manage-ment Systems (LIMS) and other computerized laboratory sys-tems The chapter includes specific interpretations of thevalidation requirements in the post-Part 11 environment

A review of standards without an examination of the terpretation and enforcement of those standards would be oflittle value In Chapter 7 therefore, the FDA’s GLP inspec-tion program is dissected and analyzed, revealing the philos-ophy and approach of the regulators to GLP field interpreta-tion

in-In each previous edition the eighth and final chapter hasbeen dedicated to the art of prediction, providing an extrapo-lation of GLP trends and applications into the near-term fu-ture These predictions have provided gratifyingly accuraterecommendations for anticipating new regulatory and practi-cal changes In this third edition, Chapter 8 looks at the nextstep in laboratory automation: robotic control of samples andanalysis, the field laboratory, new laboratory applications inDNA and other genetic testing, and emerging new govern-ment perspectives on regulation and enforcement

These eight chapters provide a detailed review of theGLP requirements, an examination of the application of

those requirements, an interpretation of the effects of GLPs

on an automated laboratory and the effects of that tion on the GLP guidelines, and a look at future trends inlaboratories and their regulation

automa-Sandy Weinberg

Copyright © 2003 Marcel Dekker, Inc.

4 The Good Automated Laboratory Practices

Gerald J Whartenby, Paul L Robinson,

and Sandy Weinberg

5 Implementing GLPs in a Non-GLP

Analytical Laboratory

Stephanie A Olexa

6 Computer Systems Validation

Re-Paul L Robinson Muhlenberg College, Allentown, sylvania, U.S.A.

Penn-Gary C Stein Weinberg, Spelton & Sax, Inc., Boothwyn,Pennsylvania, U.S.A

Jean M Taylor* U.S Food and Drug Administration,Rockville, Maryland, U.S.A

Sandy Weinberg Muhlenberg College, Allentown, sylvania, U.S.A.

Penn-Gerald J Whartenby Muhlenberg College, Allentown,Pennsylvania, U.S.A

Copyright © 2003 Marcel Dekker, Inc.

establish the safety and efficacy of biological products Theselaws place on the Food and Drug Administration (FDA) theresponsibility for reviewing the sponsor’s test results and de-termining whether or not the results establish the safety andefficacy of the product If the agency accepts that safety andefficacy are established adequately, the sponsor is permitted

to market the product

The types of scientific tests needed to establish safetyare dependent on the nature of the regulated product and itsproposed use A product such as a food or color additive willrequire tests to elucidate the potential of the product to in-duce adverse acute, subchronic, and chronic effects Thesafety tests are generally performed in animals and other bio-logical systems Both the types of tests and the methodology

of particular tests have changed over the years with scientificadvances in the field of toxicology

The FDA regulations or guidelines prescribe the types ofsafety tests for a particular product Sponsors may conductthe studies in their own laboratories or have them performed

by a contract laboratory, a university, or some other type oflaboratory The sponsor submits the study reports to the FDA

in food and color additive petitions, investigational new drugapplications, new drug applications, new animal drug appli-cations, biological product license applications, and other re-quests for permission to market a product

Food and Drug Administration scientists evaluate thesafety studies to determine whether or not the results sup-port a conclusion that the product can be used safely Untilthe mid-1970s, the underlying assumption in the agency re-view was that the reports submitted to the agency accuratelydescribed study conduct and precisely reported the studydata A suspicion that this assumption was mistaken wasraised in the agency’s review of studies submitted by a majorpharmaceutical manufacturer in support of new drug appli-cations for two important therapeutic products Review scien-tists observed data inconsistencies and evidence of unaccept-able laboratory practices in the study reports

The FDA’s Bureau of Drugs requested a “for-cause” spection of the manufacturer’s laboratories to determine thecause and extent of the discrepancies A for-cause inspection

in-is one initiated at the request of an agency unit when there

is reason to suspect a problem in an FDA-regulated product.The authority to make for-cause inspections is a general oneunder the FFDCA, but one that had rarely been applied toanimal laboratories

In a statement in a Senate hearing on July 10, 1975,

Dr Alexander M Schmidt, commissioner of food and drugs,reported the preliminary results of further agency investiga-tions [1] The findings indicated defects in design, conduct,and reporting of animal studies For-cause inspections wereconducted at several laboratories and revealed similar prob-lems The nature and extent of the findings in these inspec-tions raised questions about the validity of studies being sub-mitted to the agency

The deficiencies observed in these inspections were marized in the preamble to the proposed good laboratorypractice regulations [2] as follows:

sum-1 Experiments were poorly conceived, carelessly cuted, or inaccurately analyzed or reported

exe-2 Technical personnel were unaware of the importance

of protocol adherence, accurate observations, rate administration of test substance, and accuraterecord keeping and record transcription

accu-3 Management did not assure critical review of data

or proper supervision of personnel

4 Studies were impaired by protocol designs that didnot allow the evaluation of all available data

5 Assurance could not be given for the scientific fications and adequate training of personnel in-volved in the research study

quali-6 There was a disregard for the need to observe properlaboratory, animal care, and data management pro-cedures

7 Sponsors failed to monitor adequately the studiesperformed in whole or in part by contract testing lab-oratories.

8 Firms failed to verify the accuracy and completeness

of scientific data in reports of nonclinical laboratorystudies in a systematic manner before submission tothe FDA

The problems were so severe in Industrial Bio-Test oratories (IBT) and Biometric Testing Inc that both labora-tories ceased doing preclinical studies Industrial Bio-TrustLaboratories had been one of the largest testing laboratories

Lab-in the United States, with thousands of its studies servLab-ing tosupport the safety of drugs, pesticides, and food additives.The FDA and the Environmental Protection Agency (EPA)began reviewing all the compounds that relied on IBT andBiometric Testing Inc studies for support of safety Theagencies required the study sponsors to submit outside audits

of the study data From the audits of the IBT studies, EPAfound 594 of 801 key studies, or 85% to be invalid [3] TheFDA’s Bureau of Foods found 24 of 66 IBT studies, or 36% to

be invalid [4]

Criminal charges of fraud were brought against four IBTofficials Three of the officials were convicted; a mistrial wasdeclared in the case of the fourth official because of illness [5]

FDA’S RESPONSE TO THE PROBLEM

The conclusion that many studies on which the safety of ulated products had been based could be invalid was alarm-ing to the FDA, the EPA, Congress, the public, and industry.Commissioner Schmidt established the Bioresearch Monitor-ing Program in early 1976 to develop a program that woulddeal with the problem of data validity not only in the area ofsafety studies but also in clinical testing Congress voted a

reg-special appropriation of $16 million and additional personnel

to support the program

A steering committee, chaired by the associate sioner for compliance and composed of the associate commis-sioners, the bureau directors, the chief counsel, the director

commis-of the National Center for Toxicological Research, and the ecutive director for regional operations, directed the program.Four task forces—the Toxicology Laboratory Monitoring TaskForce, the Investigator Sponsor Task Force, the InstitutionalReview Committee Task Force, and the Administrative TaskForce—handled different components of the program The re-sponsibility for developing a strategy to ensure the validityand reliability of all nonclinical laboratory studies to supportthe safety of FDA-regulated products was assigned to theToxicology Monitoring Task Force This task force was in-structed to inventory all firms submitting research to theFDA and other involved federal agencies; to develop formalagreements with other agencies for the inspection of labora-tories; to develop and publish standards for measuring theperformance of research laboratories; to develop agencywideenforcement strategies; and to develop plans for hiring, train-ing, and assigning the new employees authorized by Con-gress for the program

ex-The Toxicology Monitoring Task Force chose the tion of GLP regulations as the best approach for assuringstudy validity Six other approaches were considered butwere discounted as not feasible or efficient

publica-• One approach would have been to continue the gram of for-cause inspections, but they would be trig-gered only by perceived deficiencies in the data aftersubmission to the agency, and thus would not haveprovided systematic assurance that all studies werevalid or guidance to laboratories on standards forconduct of studies

pro-• A second approach would have been to shift bility for nonclinical testing of regulated products to

responsi-the FDA Such a shift would have required sional authorization, because the FFDCA clearlyplaces this responsibility on the sponsor of the prod-uct In addition, the costs of such a shift would havebeen prohibitive.

congres-• The third approach considered was for the agency topublish detailed test protocols and procedures forstudies on regulated products This, however, wouldhave discouraged the use of informed scientific judg-ment in designing tests and inhibited the develop-ment of new toxicological methods

• Another approach would have been to establish censing procedures for testing laboratories, but devel-oping uniform licensing criteria would have been verydifficult, considering the variety of regulated prod-ucts, test types, and laboratory facilities

li-• Still another approach was the establishment of afull-time, on-site inspection program for laboratoriessimilar to the U.S Department of Agriculture’s in-spections of meat-processing plants Such a programwas considered to be an inefficient use of the FDA’sinvestigational resources, because many testing facil-ities are too small or too diversified to justify full-time, on-site monitoring

• Consideration was also given to the publication ofGLP guidelines rather than regulations While thiswould have provided the testing facilities with stan-dards of conduct, it would not have given the agency

an enforcement mechanism to ensure that the dards were met

stan-The regulations approach had several advantages Itwas within the legal mandates of the agency and allowed effi-cient use of agency resources for ensuring compliance It wasalso similar to the use of good manufacturing practice (GMP)regulations with which most of the regulated industries werealready familiar The main advantage, however, was that the

regulations approach focused on the process by which testingfacilities carried out studies rather than on the product beingtested or the studies themselves The use of scientific judg-ment in the planning and conduct of safety studies thus wasnot hampered, and the detail required for a focus on specificstudies, or kinds of studies, was avoided.

Once the decision to establish GLP regulations had beenmade, a subcommittee was appointed to draft the regula-tions This subcommittee was composed of individuals repre-senting all the FDA bureaus and a variety of scientific disci-plines The subcommittee began its work with a rough draftthat had already been prepared by personnel in the Bureau

of Drugs This early draft had used two independent, ited sets of GLP guidelines submitted by G D Searle and

unsolic-Co and the Pharmaceutical Manufacturers Association Thesubcommittee’s first draft was circulated to all FDA bureausfor comment, revised on the basis of these comments, andthen circulated to other government agencies for comment.The subcommittee considered these comments in preparingthe final draft, which was published as the proposed GLPregulations on November 19, 1976 The proposed regulationswere designated as a new part 3.e of Chapter 21 of the Code

of Federal Regulations, but the final regulations were fied as part 58 (21 CFR Part 58)

codi-FDA’S PROPOSED REGULATIONS

The purpose of the GLP regulations is to assure the qualityand integrity of the data submitted to the FDA in support

of the safety of regulated products To this end, most of therequirements of the proposal would have been considered fa-miliar and reasonable by any conscientious scientist Proto-cols and standard operating procedures (SOPs), adequatefacilities and equipment, full identification of test substances,proper animal care, equipment maintenance, accurate re-cording of observations, and accurate reporting of results are

basic necessities for the conduct of a high-quality, valid ity, or any scientific study The proposed regulations alsoplaced a heavy emphasis on data recording and record andspecimen retention to ensure that a study could be recon-structed at a later time if the need arose.

toxic-The proposed regulations went beyond these basic quirements for a valid study by requiring each study to have

re-a study director who would hre-ave “ultimre-ate responsibility forimplementation of the protocol and conduct of the study”[§ 3e/31(a)], and each testing facility to have a quality assur-ance unit to monitor conduct of studies The concept of aquality assurance unit to monitor study conduct was a newone to most laboratories but a familiar one in manufacturingfacilities operating under various GMP regulations

In addition, because the GLPs were regulations, the posal identified the scope of the regulations, the authority un-der which they were promulgated, and the strategy for theirenforcement

or marketing permit.” This latter term was a means of ferring to the numerous categories of data required to besubmitted to the agency, such as food and color additive peti-tions, new drug applications, and new animal drug applica-tions The studies covered by the regulations included allkinds of toxicity studies—from in vitro mutagenicity studies

re-to acute, subchronic, and long-term re-toxicity/carcinogenicity

studies—in which inadequate effectiveness might affectsafety Studies excluded from the scope of the regulationswere those utilizing human subjects, clinical studies or fieldtrials in animals, basic exploratory studies, or studies to de-termine physical or chemical properties of a test substanceindependent of a test system.

The proposal recognized that the scope might justifiably

be defined on a different basis, possibly on a facilities basis,and asked for comments on whether specific types of testingfacilities might be excluded from coverage by the regulations

Enforcement Strategy

The basic mechanism of enforcement was to be inspection oftesting facilities by FDA field investigators The FDA’s au-thority to conduct inspections of facilities engaged in inter-state commerce of regulated products is well established, andsuch inspections are the primary method of enforcement ofthe FFDCA Under the proposal, studies performed by a test-ing facility that refused to permit inspection would not be ac-cepted in support of an application for a research or market-ing permit

At the conclusion of an inspection, the FDA investigatornotifies the facility of any deficiencies identified during theinspection, both in writing (on Form 483, “Notice of Inspec-tional Observations”) and in discussion with management Ifthe deficiencies were of a kind that might affect study valid-ity, more formal warnings would be issued to the testing fa-cility through a regulatory letter or a notice of adverse find-ings

Initial planning under the Bioresearch Monitoring gram called for each testing facility to be inspected yearly Itwas later decided that a biennial inspection would suffice toensure that all 2-year studies would be inspected at leastonce while in progress

Pro-When deficiencies were extensive enough to affect thevalidity of a study, the proposal provided that the study

would not be considered by the FDA in support of a research

or marketing permit The proposal noted that the data fromsuch a study had to be submitted to the agency, however, andthat if they were adverse to the product might still be used

as a basis for regulatory action This difference in treatmentwas justified by the consideration that a bad study might re-veal an adverse effect but could not establish the absence of

an adverse effect

The final and most severe enforcement strategy underthe proposal was the disqualification of a testing facility.Data from a disqualified facility would not be accepted insupport of a research or marketing permit The agencyviewed this penalty as one that would only be employed incases in which the testing facility had severe, widespread de-ficiencies that raised questions about the validity of all thestudies performed in the facility and in which previous regu-latory efforts had failed to bring the facility into compliancewith the regulations Unlike the other enforcement strate-gies, there was no specific authority for disqualification; theGLP regulations themselves established this authority

Authority

The GLP regulations were issued under the general mandate

of section 701(a) of the FFDCA, which empowers the sioner to promulgate regulations for the efficient enforcement

commis-of the act The commissioner’s power to issue regulations fordetermining that a clinical investigation of a drug intendedfor human use be scientifically reliable and valid [21 CFR314.111(a)(5)] had been upheld by the Supreme Court in the

decision Weinberger v Hynson, Westcott and Dunning, Inc.,

412 U.S 609 (1973) The clinical investigations regulationshad also been issued under section 701(a) of the FFDCA Itwas further considered that the authority to issue GLP regu-lations gave the agency the authority to establish the terms

on which it would accept nonclinical testing data; thereforethe proposed regulations provided for the rejection of studies

if the testing facilities refused to permit inspection The FDAalready had the authority to compel inspection of nonclinicallaboratories doing work on new drugs, new animal drugs, ormedical devices The FDA may inspect both manufacturingestablishments and laboratories concerned with drugs anddevices and examine research data on these products undersection 704(a) of the FFDCA.

COMMENTS ON THE PROPOSAL AND

THE FINAL REGULATIONS

More than 1000 individual items were contained in 22 oralresponses from a 2-day public hearing and 174 written re-sponses to the proposal Many responses commented on bothgeneral issues, such as scope, and specific details in individ-ual sections and paragraphs The preamble to the final regu-lations addressed these comments in detail, and modifica-tions, both substantial and editorial, were included in thefinal regulations, which were issued on December 22, 1978,and became effective June 20, 1979 [6]

Management and the Study Director

As outlined in the proposal, comments on the responsibilities

of the study director identified many of these responsibilities

as the prerogative of management In response to these ments, a new section (§ 58.31) was included in the final regu-lations This section established that if necessary, the man-agement of the testing facility had the responsibility fordesignating and replacing the study director; for providing

com-a qucom-ality com-assurcom-ance unit com-and com-assuring the com-actions to correctdeviations reported by the quality assurance unit are taken;for assuring that the personnel and the tools (e.g., facilitiesand equipment) are available as needed; and for assuringthat test and control articles are appropriately identified.Despite making management responsible for many ar-eas that the proposal had assigned to the study director, the

final regulations retained the concept of the study director asthe single focus of responsibility for study conduct by redefin-ing the function of the study director as “overall responsibil-ity for the technical conduct of the study, as well as for theinterpretation, analysis, documentation and reporting ofresults, and represents the single point of study control”(§ 58.33).

The Quality Assurance Unit

Not surprisingly, many comments objected to the ment for a quality assurance unit on the basis of increasedcosts, administrative burden, and interference with manage-ment prerogatives and informed scientific judgment of studydirectors An alternative solution for study monitoring wasnot suggested, however

require-The FDA retained the requirement for a quality ance unit, or function, to monitor studies for conformance tothe regulations It was emphasized that the function was ad-ministrative rather than scientific The personnel responsiblefor quality assurance for a given study were required to beseparate from, and independent of, the personnel responsiblefor the direction and conduct of that study

assur-Many commentators wanted the inspection records piled by the quality assurance unit excluded from the records

com-to be inspected by the agency on the basis that an inspection

“might violate the constitutional privilege against compelledself-incrimination.” The agency rejected this argument, be-cause the privilege against compelled self-incrimination isnot available to a collective entity, such as a business enter-prise, or to an individual acting as a representative of a col-lective entity The agency did, however, exclude the qualityassurance unit’s inspection records form inspection to encour-age more forthrightness in the reports The quality assuranceunit was required to certify that the inspection of studies andfinal reports had been made by means of a signed statement

to be included in the final report [§ 58.35(b)(7)]

In general, the comments on the proposed regulations soughtlimitations through exclusion of various classes of FDA-regulated products, such as medical devices; various types offacilities, such as academic and not-for-profit organiza-tions; or various types of studies, such as short-term studies.These suggestions were rejected primarily because the basicpurpose of the regulations—to ensure the validity of safetydata submitted to the agency—would have been frustrated

by excluding particular products, facilities, or studiesfrom coverage None of the commentators suggested an alter-native overall approach to defining the scope of the regula-tions

The scope adopted in the final regulations was onlyslightly changed from the proposal; the main difference wasthe exclusion of functionality studies from coverage

Inspections

The major concerns of the commentators with respect to theactual inspection of facilities were the competence and scien-tific qualifications of the FDA investigators In early inspec-tions (both the for-cause inspections prior to the proposal andthe inspections made in the pilot program under the pro-posal), the agency assigned its most experienced field investi-gators and sent agency scientists to participate in the inspec-tions To further assure the competence of the investigators,

a training program was established at the National Centerfor Toxicological Research for both field investigators and sci-entists The compliance program for the GLPs also providesfor scientific review in FDA headquarters of all GLP inspec-tion reports

That testing facilities still doubt the competence of somefield investigators was evident in a comment on the 1987 re-vision of the GLPs [7], which requested training in the GLPsfor the FDA’s field personnel

Numerous comments were made on the provisions for qualification of a testing facility (subpart K) Although theproposal stated that the agency considered that it would onlyrarely invoke this penalty, it appeared from the objectionsthat industry had interpreted these provisions to mean theagency would invoke disqualification frequently and for mi-nor failures to comply with the regulations On the basis ofthe objections, the sections of subpart K on purpose (§ 58.200)and the grounds for disqualification (§ 58.202) were exten-sively revised The revision stated that the purposes of dis-qualification were as follows:

dis-1 To permit the exclusion of completed studies fromconsideration in safety evaluation until it could beshown that noncompliance with the regulations didnot affect the validity of the study data

2 To permit the exclusion of studies completed after qualification from consideration in safety evaluationuntil the facility could demonstrate that it would con-duct studies in compliance with the regulations.Three grounds for disqualification were given in the fi-nal regulations; all three must be present to justify disqualifi-cation

dis-1 Failure of the facility to comply with one or more ofthe GLP regulations or other regulations applying tofacilities published in Chapter 21 of the Code of Fed-eral Regulations

2 Adverse affects on the validity of the studies

3 Failure to achieve compliance with regard to lesser ulatory actions, such as warnings or rejection of studies

reg-EVALUATION OF THE FDA PROGRAM

The proposed GLP regulations announced that based on therequirements of the proposal, the FDA would conduct a num-ber of surveillance inspections of testing facilities during No-

vember and December of 1976 and January of 1977 Theseinspections had the dual purpose of determining the status

of the laboratories and evaluating the work ability of the posed regulations The results of this pilot inspection pro-gram were analyzed and published by the FDA’s Office ofPlanning and Evaluation [8]

pro-Forty-two laboratories were identified for inspection.Ongoing and completed studies would be examined as avail-able The inspections used a checklist that was divided intotwo parts, one part covering laboratory operations and theother study conduct The checklist arbitrarily placed mixingand storing of test substances in the area of laboratory opera-tions and distribution and characterization of the substances

in study conduct

In the completed survey, only 39 laboratories, with 67studies, yielded usable data Twenty-three of the testingfacilities were sponsor laboratories, 11 contract laboratories,and five university laboratories Forty-eight of the studieswere completed and 19 ongoing The findings showed thatsponsor laboratories met 69% of the requirements, the con-tract laboratories met 56% of the requirements, and univer-sity laboratories met only 46% of the requirements

Requirements in the areas of facilities, animal care, andpersonnel were the most often met, while the fewest require-ments were met in the areas of the quality assurance unit, mix-ing and storage of the test substances, and record retention.Ongoing studies showed better adherence (73% of the re-quirements met) than did completed studies (57%) Animalcare and test substance distribution showed the greatest de-gree of adherence Low degrees of adherence were found inthe quality assurance function and protocol-related require-ments The comments of the agency investigators indicatedthat testing facilities were already making changes in theirongoing studies to bring them into compliance

Following publication of the final regulations, a secondsurvey was conducted to measure compliance against the fi-nal requirements [9] The study sample consisted of 17 spon-

sor laboratories, 10 contract laboratories, and one universitylaboratory The average compliance rate was 88%, with thedeficiencies observed in sponsor and contract laboratoriesshowing little difference Compliance was measured both bythe average compliance rate with the requirements of a sec-tion of the regulations or by the number of laboratories fail-ing to meet one or more of the section’s requirements Thefollowing sections showed high compliance by both measure-ments: personnel, management, study director, general facili-ties, and facilities for animal care, handling of test andcontrol articles, laboratory operations, specimen and datastorage, record retention, and personnel and administration.Areas that showed low compliance by the same measureswere quality assurance units, maintenance and calibration ofequipment, SOPs, animal care (primarily the failure to ana-lyze feed and water for interfering contaminants), test andcontrol article characterization, mixtures of articles with car-riers, study protocol, and study conduct (primarily failure tosign and date data sheets or to follow the protocol).

The results of these surveys indicated both the ity of the regulations and the success of the vigorous effortsthat most testing facilities were making to achieve compli-ance The record of compliance continued to be good In its

practical-1984 update of compliance results [10], the FDA reportedthat 72% of the inspection reports since 1976 showed few or

no substantial deviations from the regulations and 23%showed minor to significant deviations that could be cor-rected voluntarily by the testing facility Four percent of thereports, however, showed significant deviations requiringcorrective action within a specified period of time, and stud-ies are still occasionally rejected because significant devia-tions render them invalid

THE PROBLEM FROM EPA’S PERSPECTIVE

The EPA had concerns similar to those of the FDA Undersection 4 of the Toxic Substances Control Act (TSCA), theEPA evaluates laboratory data submitted to the agency re-

garding tests of the health effects of chemical substances andmixtures Also, under authority of the Federal Insecticide,Fungicide and Rodenticide Act (FIFRA), the EPA evaluateslaboratory test data relating to hazards to humans arisingfrom the use of a pesticide product when the agency evalu-ates pesticide registration applications.

The EPA was aware of the problems the FDA had ered in the mid-1970s relating to unacceptable laboratorypractices The EPA responded to the FDA’s findings by form-ing the toxicology auditing program in the agency’s Office ofPesticide Programs The EPA also held public hearings to so-licit comments on how appropriate the agency’s approach was

uncov-to data quality assurance for pesticide testing

In 1978, the EPA and FDA formalized both agencies’commitment to establish a coordinated quality assurance pro-gram through an interagency agreement Under this agree-ment, the FDA provided assistance during EPA data audits.Between 1978 and 1979, the agencies performed 65 jointaudits that indicated that some testing facilities did not fol-low GLPs The EPA referred some of these facilities to theDepartment of Justice for prosecution

EPA’S PROPOSED REGULATIONS

Like the FDA, the EPA considered different approaches toassure that data submitted to the agency complied with nec-essary quality standards

Licensing or certification of laboratories was consideredimpractical for toxicology laboratories because of thegreat diversity and range of testing capabilities andthe complex quality control procedures used in toxicol-ogy testing

A voluntary standard-setting scheme administered bythe private sector was rejected because such schemeswere considered practically unenforceable

Like the FDA, the EPA determined that the tion of GLP regulations would most effectively handle the

promulga-problem of compliance with adequate control standards, andthe agency published proposed health effects standards fortesting under TSCA on May 9, 1979 [11] Proposed GLP regu-lations applicable to laboratory studies submitted to the EPA

in compliance with FIFRA were published on April 18, 1980[12] Supplemental GLP standards for the development ofdata on physical, chemical, persistence, and ecological effects

of chemical substances for which the EPA requires testingunder section 4 of TSCA were published on November 21,

1980 [13] The EPA took this action because the previouslypublished GLPs for health effects testing did not address theanalytical problems associated with physical, chemical, andpersistence testing

Differences Between EPA Proposed Regulations and

FDA Regulations

When it issued proposed GLP regulations in 1978 and 1980,the EPA harmonized those regulations that the final GLPregulations which had been issued by the FDA in 1978 Therewere major differences, however, because the two agencies’approaches to regulating laboratory studies differed The spe-cific working of various sections of the EPA’s proposed regu-lations varied from those of the FDA because of the differingscope of the authority of each agency

EPA’s Final Regulations

The EPA’s FIFRA and TSCA GLP regulations were both sued in final form on November 29, 1983 [14] The FIFRAGLP regulations were codified as 40 CFR 160, and the TSCAGLP regulations as 40 CFR 792 In terms of the TSCA GLPs,the final regulations incorporated the proposed GLPs issued

is-on May 9, 1979 and November 21, 1980

GLP REVISIONS IN THE 1980S

FDA Revisions

In 1984, the FDA proposed revising its 1978 GLP regulations.The rationale for this revision was to clarify, amend, or delete

provisions of the regulations in order to reduce the regulatoryburden on testing facilities.

During agency inspections, the FDA had found thatmost laboratories were complying with the GLP require-ments—indeed, that the violations it had noted in the mid-1970s were the exception, rather than the general rule—andthe agency thought that it could streamline the regulationswithout compromising the GLP program The FDA had alsoreceived comments and questions about the GLP regulationsthat indicated that several GLP provisions did not signifi-cantly contribute to the quality and integrity of data submit-ted to the agency At the same time, the agency was under-taking a review of its regulations to minimize regulatoryburdens

The FDA established a GLP review task team to identifyprovisions in the regulations that could be amended or de-leted, and this team recommended revisions to 36 GLP provi-sions Recommendations were issued as a proposed rule onOctober 29, 1984 [15] The proposal made various changes todefinitions to reduce the amount of paperwork required fornonclinical laboratory studies and to clarify earlier GLP pro-visions Similar clarifications were made to the provisions,delineating the definition and function of the study directorand quality assurance unit

In the 1984 proposal, changes were also made to informcollection requirements subject to the Paperwork ReductionAct of 1980 Modifications were made to the provisions re-garding animal care, animal supply, and administrative andpersonnel facilities Provisions regarding equipment design,maintenance and calibration of equipment, SOPs, animalcare, test and control article characterizations, and mixtures

of articles with carriers were changed to allow more ity of laboratory operations The section on laboratory proto-cols was amended to eliminate unnecessary entries by allow-ing laboratories to identify the information applicable to thearticles being tested The agency also deleted the require-ments that the selection of the test system be justified in theprotocol Other changes to the GLP regulations involved revi-

flexibil-sions to proviflexibil-sions regulating conduct of laboratory studiesand the storage, retrieval, and retention of records.

The FDA received 33 comments on its proposed GLP visions After considering these comments, the agency issuedits final GLP provisions on September 4, 1987 [16] Some ofthe comments received by the agency indicated a need to addnew terms to the definition section of the regulations (e.g.,

re-study initiation and re-study completion), while others

encour-aged the FDA to retain the original GLP language in certainprovisions rather than make the amendments the agency hadproposed in 1984

EPA Revisions

Among the comments received by the FDA, eight commentsurged the agency to encourage the EPA to adopt similar revi-sions to its GLP regulations, which were now more stringentthan the FDA’s regulations The FDA stated that the agencyconsulted with the EPA regarding the changes made to theFDA’s regulations, and that the FDA would cooperate withthe EPA when the latter agency revised its own GLP regula-tions As a result of its own monitoring of GLP compliance,EPA agreed that its own GLP regulations could be stream-lined without compromising the integrity of data submitted

to the agency

The EPA’s proposed revisions to its FIFRA and TSCAGLP regulations were issued on December 28, 1987 [17] TheEPA agreed with the FDA that many GLP provisions could

be amended to incorporate the changes that had been made

by the FDA In addition, the scope of the FIFRA regulationswas expanded to include environmental testing provisionsthat already existed in the TSCA GLPs, and to include prod-uct performance data (efficacy testing) The EPA also pro-posed changes Some changes were made to the proposed reg-ulations in response to these comments, such as exemptingfrom routine EPA inspections the records of quality assur-ance unit findings and problems, as well as records of correc-

tive actions recommenced and taken, except under specialcircumstances The final versions of EPA’s revisions to itsGLPs were issued on August 18, 1989 [18].

The EPA’s proposed GLP revisions basically conformed

to the charges the FDA had made in the latter agency’s finalrule of September 4, 1987 The major differences between theEPA proposals and the FDA GLPs continued to reflect thevarying needs and responsibilities of each agency and the ex-panded scope of the EPA’s regulations in light of the testingand test systems affected under the EPA’s authority to re-quire test data in support of research or marketing permits

to include ecological effects, environmental and chemical fate,and efficacy testing in addition to health effects testing.Other federal agencies, as well as international agenciesand organizations, also developed GLP programs The Na-tional Toxicology Program concluded that studies performedunder contract to the program should be performed in compli-ance with GLPs, and established a quality assurance function

to monitor the laboratories and studies In 1981, the zation for Economic Cooperation and Development (OECD)developed GLP principles for studies performed for the Euro-pean Economic Community (EC) countries Between 1986and 1988, EC council directives adopted the OECD and re-quired that all EC countries monitor and verify compliancewith those standards

Organi-In 1982, the Japanese Ministry of Health and Welfareissued GLP standards for safety studies on drugs This wasfollowed in 1984 by GLP standards issued for studies on in-dustrial chemicals by the Japanese Ministry of InternationalTrade and Industry and GLP standards for toxicological stud-ies on agricultural chemicals by the Japanese Ministry ofAgriculture, Forestry, and Fisheries There are differences inthese regulations and guidelines that pose problems for spon-sors planning studies to meet the requirements of differentagencies or countries [19]

As a solution to part of this problem, the FDA has oped memoranda of understanding (MOUs) with Canada

devel-(1979), Sweden devel-(1979), Switzerland (1985), France (1986),Italy (1988), Germany (1988), the Netherlands (1988), andthe United Kingdom (1988) These MOUs acknowledge mu-tual recognition of the adequacy of inspectional programs inthe participating countries and permit the exchange of databetween the countries without need for independent verifica-tion by the recipient country.

REFERENCES

Food and Drug Administration, Public Health Service, ment of Health, Education and Welfare before the Subcommit- tee on Health, Committee on Labor and Public Welfare and Subcommittee on Administrative Practice and Procedure, Committee on the Judiciary, U.S Senate, July 10, 1975.

Depart-2 Department of Health, Education and Welfare, Food and Drug Administration Nonclinical laboratory studies: Proposed reg-

ulations for good laboratory practice Fed Reg 41:51205–

51230, 1976.

3 Environmental Protection Agency, Office of Pesticide grams Summary of the IBT Review Program July 1983.

Pro-4 Survey by Dr Jean M Taylor.

5. IBT data falsification Food Chem News 25(24):2, 1983.

6 Department of Health, Education and Welfare, Food and Drug

Administration Good laboratory practice regulations Fed Reg

43:59985–60024, 1978.

7 Department of Health, Education and Welfare, Food and Drug

Administration Good laboratory practice regulations Fed Reg

52:33767–33782, 1987.

8 Food and Drug Administration, Office of Planning and ation OPE Study 42: Results of the Nonclinical Laboratory Good Laboratory Practices Pilot Compliance Program Sept 1977.

Evalu-9 Food and Drug Administration, Office of Planning and ation OPE Study 49: Results of the Toxicology Laboratory In- spection Program (Jan.–March 1979) July 1979.

Evalu-10 Department of Health, Education and Welfare, Food and Drug Administration 21 CFR Part 58: Good laboratory practice reg-

ulations: Proposed rule Fed Reg 49: 43529–43537, 1984.

11 Environmental Protection Agency Good laboratory practice

standards for health effects: Proposed rule Fed Reg 44:

27362–27375, 1979.

12 Environmental Protection Agency Pesticide programs, lines for registering pesticides in the United States: Proposed good laboratory practice guidelines of toxicology testing, pro-

Guide-posed rule Fed Reg 45:26373–26385, 1980.

13 Environmental Protection Agency Physical, chemical, sistence, and ecological effects testing: Good laboratory

per-practice standards, proposed rule Fed Reg 45:77353–77365,

1980.

14 Environmental Protection Agency Toxic substances control:

Good laboratory practice standards; Final rule Fed Reg 48:

53921–53944, 1983: Environmental Protection Agency cides program; Good laboratory practice standards: Final rule.

Pesti-Fed Reg 48:53945–53969, 1983.

15 Food and Drug Administration Good laboratory practice

regu-lations: Proposed rule Fed Reg 49:43530–43537, 1984.

16 Food and Drug Administration Good laboratory practice

regu-lations: Final rule Fed Reg 52:33768–33782, 1987.

17 Environmental Protection Agency Federal Insecticide, cide and Rodenticide Act (FIFRA): Good laboratory practice

Fungi-standards, proposed rule Fed Reg 52:48920–48933, 1987;

En-vironmental Protection Agency Toxic Substances Control Act (TSCA): Good laboratory practice standards, proposed rule.

Fed Reg 52: 489933–48946, 1987.

18 Environmental Protection Agency Toxic Substances Control Act (TSCA): Good laboratory practice standards, final rule.

Fed Reg 54: 34034–34050, 1989; Environmental Protection

Agency Federal Insecticide, Fungicide and Rodenticide Act

(FIFRA): Good laboratory practice standards, final rule Fed Reg 54:34052–34074, 1989.

19 For differences in worldwide GLP standards, see Chapter 3 of

this book and also RS DeWoskin, SM Taulbee International GLPs Interpharm Press, 1993.

Copyright © 2003 Marcel Dekker, Inc.

FDA/GLP Regulations

WENDELL A PETERSON

Parke-Davis Pharmaceutical Research Division

of Warner-Lambert Company, Ann Arbor,

promul-tory language [the words current good manufacturing tice in section 501(a)(2)(B)], the term “good laboratorypractice” does not appear in the FD&C Act; rather, the GLPregulations are issued under the FDA commissioner’s impliedpowers to prescribe standards for the conduct of studies de-signed to establish the safety of products regulated by theFDA.

prac-This chapter provides a general discussion of all aspects

of FDA’s GLP regulations, as amended to September 13,

1991 Where appropriate, FDA interpretations are presentedfor specific sections of the GLP regulations For critical parts

of the regulations, a more depth discussion is provided, cluding means for implementation and an evaluation of posi-tive and negative impacts on the conduct of GLP-regulatedstudies

in-SUBPART A: GENERAL PROVISIONS

§ 58.1: Scope

(a) This part prescribes good laboratory practices for ducting nonclinical laboratory studies that support or are intended to support applications for research or market- ing permits for products regulated by the Food and Drug Administration, including food and color additives, ani- mal food additives, human and animal drugs, medical de- vices for human use, biological products, and electronic products Compliance with this part is intended to assure the quality and integrity of the safety data filed pursuant

con-to sections 406, 408, 409, 502, 503, 505, 506, 507, 510, 512–516, 518–520, 706, and 801 of the Federal Food, Drug, and Cosmetic Act and sections 351 and 354–360F

of the Public Health Service Act.

(b) References in this part to regulatory sections of the Code

of Federal Regulations are to Chapter I of Title 21, unless otherwise noted.

This preamble to the GLP regulations [2], the report of

a series of three briefing sessions on the GLP regulations that

were conducted by FDA on May 1, 2, and 3, 1979 , and thecollections of responses by Dr Paul Lepore (FDA spokesman

on GLP issues) to questions about the GLP regulations [12],have defined the types of studies to which the GLP regula-

tions apply In general, all of the following conditions must

exist before a study will be regulated by GLP:

1 Study of a product regulated by the FDA (except metics)

cos-2 In vivo or in vitro study

3 Study in which the FDA-regulated product is istered or added to nonhuman animals, plants, mi-cro-organisms, or subparts of the preceding

admin-4 Study results submitted or intended to be submitted

to FDA in support of (i.e., as the basis for) the proval of an application for a research or marketingpermit

ap-5 Study results may be used to predict adverse effects

of and/or to establish safe use characteristics for theFDA-regulated product

The FDA has made it clear that the duration of thestudy and the place where the study is conducted do not de-termine whether or not the study is GLP-regulated Thus, theGLPs apply to short-term studies (e.g., median lethal dosestudies and irritation studies) as well as long-term studiesthat meet all of the above criteria, and the GLPs apply tosuch studies whether conducted in a manufacturer’s labora-tories, in a university laboratory, or at a contract or subcon-tract facility The FDA expects GLP compliance for studiesconducted in foreign countries as well as for those conductedwithin the United States

Without attempting to provide a comprehensive listing,the following are examples of studies to which the GLPs canapply:

Ames test

E Coli mutagenicity

Sister chromatid exchangeBone marrow cytogenetic

In vivo cytogenetic

In vitro mutation

In vivo micronucleusChromosomal aberrationMedian lethal dose (LD50)Acute dermal toxicity28-day dermal toxicityDermal irritationEye irritationVenous irritationMuscle irritationIntra-arterial toleranceGuinea pig maximizationPhototoxicity

OtotoxicityDependency tests on known or suspected addictive drugsTarget animal absorption, distribution, metabolism, andexcretion (ADME)

Subchronic (up to 13 weeks’ duration, multiple dosing,any route of administration)

Chronic (6 months or longer in duration, multiple ing, any route of administration)

dos-Study of fertility in early embroyonic development viously referenced as segment I)

(pre-Perinatal/postnatal (formerly referred to as segment III)

To reiterate, the foregoing list is only intended to trate the wide range of studies that may be GLP-regulated.Examples of studies that are not within the scope of theGLP regulations include the following:

illus-Pharmacology experimentsBasic research

Dose-range finding studiesStudies to develop new methodologies

Human or animal efficacy studies

Chemical assays for quality control of commercial ucts

prod-Stability tests on finished dosage forms and productsTests for conformance to pharmacopeial standardsExploratory studies on viruses and cell biology

Tests of functionality and/or appropriateness of food ditives

ad-Tests of extract ability of polymeric materials that tact food

con-Chemical tests used to derive the specifications of keted food products

mar-Studies on medical devices that do not come in contactwith or are not implanted in humans

Tests of diagnostic products

Chemical and physical tests of radiation products

Tests conducted for the release of licensed biologicalproducts

The foregoing list is also intended to be illustrative, andnot comprehensive

A facility that conducts both GLP-regulated and GLP-regulated studies should think carefully about attempt-ing to maintain a dual standard in any one laboratory or withany one group of laboratory workers In the author’s experi-ence, such a dual standard is very difficult to maintain with-out carryover of non-GLP standards to GLP-regulated work

non-In such a case it may be far better to maintain a general GLPstandard (e.g., data collection, record keeping) for all work inthe laboratory, but perhaps allow exceptions for the non-GLPstudies in areas such as quality assurance (QA) inspectionsand analytical requirements for test and control articles andarticle/carrier mixtures

The effective date of the GLP regulations was June 20,

1979 The regulations did not apply retroactively, thereforestudies begun and completed prior to the effective date werenot required to comply with the GLPs even if submitted to

FDA on or after June 20, 1979 For studies in progress onJune 20, 1979, only those portions of the study done on orafter June 20 were required to be done in compliance withthe regulations Of course, those studies initiated on or afterthe effective date were to be done in full compliance with theGLPs.

§ 58.3: Definitions

A good understanding of the definitions in section 58.3 is ical to an interpretation of many of the other sections of theregulations

crit-An illustration of the importance of a definition to latory interpretation can be found in Environmental Protec-tion Agency (EPA) regulations issued under the ResourceConservation and Recovery Act (RCRA) Among other things,these regulations are designed to regulate the disposal of

regu-“solid waste.” Anyone relying on the normal definition of

“solid” in interpreting RCRA requirements would make agrave error, because solid is defined in RCRA to include solid,liquid, semisolid, and contained gaseous materials

Although there is nothing in the definitions section ofthe GLP regulations to rival RCRA’s rewriting of the basiclaws of chemistry and physics, a clear understanding of GLPdefinitions is essential to a proper interpretation of GLP re-quirements

As used in this part, the following terms shall have themeanings specified:

(a) “Act” means the Federal Food, Drug, and Cosmetic Act,

as amended (secs 201–902, 52 Stat 1040 et seq., as amended (21 U.S.C 321–392)).

(b) “Test Article” means any food additive, color additive, drug, biological product, electronic product, medical de- vice for human use, or any other article subject to regula- tion under the act or under sections 351 and 354–360F of the Public Health Service Act.

Note the wide range of FDA-regulated products to whichthe GLPs apply